1. Field of the Invention
The invention described and claimed herein relates to psychopharmacologically-active peptides, methods of preparing such compounds, and pharmaceutical compositions in a form suitable for therapeutic administration containing these peptides. In particular, the present invention relates to novel psychopharmacologically active peptides and peptide derivatives which have been derived from a certain fragment of the hormone .beta.-lipotropin (.beta.-LPH). .beta.-Lipotropin is a polypeptide, consisting of 91 amino-acids, which is formed in the posterior lobe of the hypophysis and shows fat-mobilising activity.
2. Description of the Prior Art and Other Information
Some .beta.-LPH fragments are already known and have been described in the literature. See, for example, the articles in Chem. & Eng. News of Aug. 16, 1976, page 18 and Nov. 15, 1976, page 26.
Thus it is known that the fragment .gamma.-lipotropin, .beta.-LPH-(1-58), possesses fat-mobilising properties just as .beta.-LPH itself. The fragment .beta.-LPH-(41-58), called .beta.-melanotropin, is capable of influencing the pigmentation of the skin by stimulating the melanocytes. The sequence .beta.-LPH-(61-91), called .beta.-endorphin, is known to possess analgesic activity, which just as that of morphine, can be antagonised by naloxone so that the assumption that both morphine and .beta.-endorphin act at the same receptor is logical and obvious.
In the meantime, it has also been found that a certain affinity for the opiate receptor is also shown by smaller peptide fragments of .beta.-endorphin, for example .beta.-LPH-(61-76) (.alpha.-endorphin), the fragment .beta.-LPH-(61-69), and the fragment .beta.-LPH-(61-65) (Met-enkephalin). See Nature 258, 577 (1975).
Affinity for the opiate receptor has also been described for the endogenous peptide Leu-enkephalin, [Leu.sup.65 ]-.beta.-LPH-(61-65), and for the synthetic D-Ala-Met-enkephalin,[D-Ala.sup.62 ]-.beta.-LPH-(61-65). See e.g. Science 194, 330 (1976).
It has furthermore already been ascertained that .beta.-endorphin, .beta.-LPH-(61-91), possesses certain psychopharmacological properties. For example, this peptide inhibits the extinction of the (active) flight response in the well-known pole-climbing test (pole jumping avoidance behavior). This property of .beta.-endorphin cannot be diminished by known morphine antagonists, such as naloxone or naltrexone, so that a conclusion to one skilled in the art that the psychopharmacological activity of .beta.-endorphin is completely independent of the opiate receptor sites in the brains, is certainly justifiable.
Apart from .beta.-endorphin, the smaller peptide fragments derived from this polypeptide, namely .alpha.-endorphin, the fragment .beta.-LPH-(61-69) and Met-enkephalin have been shown to inhibit the extinction of the flight response in a similar way.
The peptide .gamma.-endorphin, .beta.-LPH-(61-77), which only differs from .alpha.-endorphin through the presence of one extra amino-acid at the C-terminal end, has also proved to possess psychopharmacological activity albeit of a completely different nature than that of .alpha.- and .beta.-endorphin. While .alpha.-endorphin retarded this extinction of the flight response, .gamma.-endorphin was shown, in contrast, to accelerate the extinction of the flight response. It is remarkable that the mere addition of one amino-acid residue to the C-terminal part of .alpha.-endorphin should bring about such a dramatic reversal of the behavioural activity.
Surprisingly, it has now been found that peptides with an amino-acid sequence .beta.-LPH-(62-77) or closely related analogues derived from such a peptide, accelerate the extinction of the flight response to a greater extent than is the case with .gamma.-endorphin. Furthermore, these peptides according to the invention, in contrast to .gamma.-endorphin, do not possess affinity to the opiate receptors.
In U.S. Pat. No. 4,097,471 (Sarantakis) there is disclosed a peptide of the formula H-Tyr-Gly-Gly-Phe-Leu-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-OH or a salt thereof. U.S. Pat. No. 4,127,517 (Coy) discloses a peptide of the formula H-Tyr-X-[Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr]-Leu-Phe- Lys-Asn-Ala-Ile. U.S. Pat. No. 4,127,518 (Coy) discloses a peptide H-Tyr-X-[Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr]-Leu-Y, wherein Y is OH, alkoxy, amine, and salts thereof. U.S. Pat. No. 4,127,519 shows a peptide of a formula analogous to 4,127,518 wherein the Leu moiety outside the bracketed portion is replaced with Leu-Phe moiety. U.S. Pat. No. 4,127,520 also described a peptide analogous to 4,127,518, but replaces 4,127,518's Leu-Y with a Leu-Phe-Lys-Y moiety.